Methods of treating an inflammatory-related disease

Abstract

The invention relates to pharmaceutical compositions and methods of treating inflammatory-related diseases associated with pro-inflammatory cytokine expression and / or reduced expression of anti-inflammatory cytokines. The method typically comprises administration of one or more compounds selected from isoindigo, indigo, indirubin, or derivatives thereof, such as, Meisoindigo and NATURA. Preferably the pharmaceutical composition comprises one or more compounds selected from isoindigo, indigo, indirubin, or derivatives thereof, an anti-inflammatory agent, and a pharmaceutically acceptable carrier.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application is a continuation-in-part of U.S. patent application Ser. No. 10 / 754,547, filed Jan. 12, 2004 and U.S. patent application Ser. No. 10 / 864,458, filed Jun. 10, 2004, which is a continuation of International Application PCT / US02 / 39866 filed Dec. 13, 2002, which claims the benefit of U.S. Provisional Application No. 60 / 407,267 filed Sep. 3, 2002 and is a continuation-in-part of the U.S. patent application Ser. No. 10 / 021,589, filed Dec. 13, 2001, now U.S. Pat. No. 6,566,341, the content of each which is expressly incorporated herein by reference thereto.TECHNICAL FIELD [0002] The invention relates to pharmaceutical compositions and methods of treating inflammatory-related diseases associated with pro-inflammatory cytokine expression and / or reduced expression of anti-inflammatory cytokines. The method typically comprises administration to a subject in need thereof one or more compounds selected from isoindigo, indigo, indiru...

AI Technical Summary

Benefits of technology

[0026] The present invention provides pharmaceutical compositions and methods of treating various inflammatory-related diseases associated with cytokine expression levels in animals using Meisoindigo and other derivatives of isoindigo, indigo and indirubin to inhibit expression of pro-inflammatory cytokines. These compositions and methods allow for the treatment of a variety of inflammatory-related diseases with minimal side effects. One of the most important advantages of the present invention is that the therapeutic compounds not only address symptoms of various inflammatory-related diseases, but also modify the diseases through suppression of expression / secretion of multiple pro-inflammatory cytokines (IL-1α, β, IL-2, IL-3, IL-6, IL-7, IL-9, IL-12, IL-17, IL-18, TNF-α, LT, LIF, Oncostatin, or IFNc1α, β, γ) and / or by stimulation of expression anti-inflammatory cytokines (IL-4, IL-10, IL-11, W-13 or TGFβ).

[0027] The present invention often results in a cure instead of simply a temporary remission of the disease symptoms. In contrast, the existing therapies for inflammatory-related diseases, in most cases, only relieve the symptoms for a short duration. Furthermore, the therapeutic compounds of the present invention are small molecules that are simple, chemically stable, and are substantially easy to produce and administer. Furthermore, Applicants have found that comparatively low dosages / concentrations of the compounds are generally sufficient to substantially inhibit the pro-inflammatory cytokines in the patient, reducing the risk of side effects associated with treatment.

Problems solved by technology

Some diseases in advanced stages can be life threatening.

Several methodologies are available for the treatment of such inflammatory diseases; the results, however, are generally unsatisfactory as evidenced by a lack of efficacy and drug related side effects associated therewith.

It either spares the rectum, or causes inflammation or infection with drainage around the rectum.

Patients with prolonged UC are at an increased risk of developing colon cancer.

There is currently no satisfactory treatment, as the cause for IBD remains unclear although infectious and immunologic mechanisms have been proposed.

Long-term therapy may cause liver damage (fibrosis or cirrhosis) and bone marrow suppression.

Also patients often become refractory to such treatment.

Psoriasis may also cause intense itching and burning.

However, they are generally considered to be only disease suppressive and disease modifying.

And none of them are curative.

Moreover, many treatments are either cosmetically undesirable, inconvenient for long-term use, or associated with significant toxicity.

Potential side effects for TNF-α inhibitor, however, are severe, including development of lymphoma (24), worsening congestive heart failure, resulting in a serious infection and sepsis, and exacerbations of multiple sclerosis and central nervous system problems (25, 26).

Immunosuppressive agents have the potential to increase the risk of infection, reactivate latent, chronic infections or increase the risk of cancer development.

Although many advances have been made in the understanding of the biological properties of psoriasis over the past 2 decades and an unconventional treatment for psoriasis has become available as described above, much of the suffering it produces is still not adequately addressed.

The inflammatory cells can also invade and damage bone and cartilage.

The joint involved can lose its shape and alignment, resulting in loss of movement.

Conventional treatment is unfortunately inefficient in RA (29).

Also, these medications carry a risk of serious adverse effects.

The therapeutic effects of the disease-modifying antirheumatic drugs (DMARDs) such as Methotrexate (MTX) are often inconsistent and short-lived.

While providing significant efficacy and a good overall safety profile in the short and medium term in many patients with RA, these biologic treatments may create serious problems and long-term side effects, such as on the liver, and still need to be evaluated.

While anti-TNF antibodies have shown protective effects in experimental autoimmune encephalomyelitis (EAE), they aggravate the disease in MS patients, suggesting that inhibition of TNF-α alone is not sufficient (33).

It seriously affects a person's ability to carry out daily activities.

PK is caused by the degeneration of the pigmented neurons in the substantia nigra of the brain, resulting in decreased dopamine availability.

The causes of these neurodegenerative disorders are unknown and there is currently no cure for the disease.

Positive response of CD patients treated with IL-10 demonstrates that there might also be an imbalance between the production of pro-inflammatory and anti-inflammatory cytokines in CD.

For example, chemokines, a family of immune molecules related to IL-8 contains approximately 50 ligands and 20 receptors, often acting with redundancy, thus making selection of appropriate specific antagonists not only difficult, but lacking in long-term efficacy.

In addition, currently marketed products or products under development are mainly protein-based agents, which are expensive to produce and inconvenient to administer (i.e., infusion).

Images